NORD gratefully acknowledges Dr. Ross Reife, Dr. Or Kakhlon, Dr. Orhan Akman and Jeffrey Levenson, APBD Research Foundation, for assistance in the preparation of this report.
Adult polyglucosan body disease (APBD) is a rare, genetic disorder characterized by a deficiency of glycogen-branching enzyme, resulting in the accumulation of polyglucosan bodies in muscle, nerve and various other tissues of the body. Polyglucosan bodies are composed of large, complex, sugar-based molecules. APBD may be characterized by dysfunction of the central and peripheral nervous systems. The central nervous system (CNS) refers to the brain and spinal cord. The peripheral nerves extend from the CNS to muscles, glands, skin, sensory organs, and internal organs. Peripheral nerves include motor nerves; sensory nerves; and nerves of the autonomic nervous system, which are involved in involuntary body functions. In individuals with APBD, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; progressive urinary difficulties; occasionally mild cognitive impairment or dementia; deficiencies in the autonomic nervous system; and/or other abnormalities. APBD is caused by mutations in the glycogen branching enzyme gene (GBE1) and is inherited in an autosomal recessive pattern.
APBD was first described in the medical literature as a clinical entity in 1980 (Robitaille Y et. al). The mutation that causes the disorder is in the same gene that causes Andersen's disease (glycogen storage disease type IV), a severe liver disorder that affects infants. The only difference is that in Andersen's disease, GBE is completely dysfunctional, whereas in APBD it retains some residual activity.
Symptoms and severity can vary greatly from one person to another. Typically, symptoms develop around the fifth decade of life. The initial sign is many times related to neurogenic bladder: specifically, an increased need to urinate that may eventually progress to cause a near complete loss of bladder control (urinary incontinence). In some cases, urinary difficulties may precede other symptoms by one or two decades.
Another common early sign of APBD disease is a feeling of numbness or weakness in the hands and feet (paresthesia). Affected individuals may experience an inability to lift the front part of the foot (foot drop), which results in the need to drag the front of the foot on the ground when walking. Affected individuals may experience weakness in the arms and legs. Eventually, affected individuals may develop progressively increased muscle tone and stiffness of the legs (spasticity), causing difficulty walking. Most individuals may eventually need assistance walking (e.g., cane or walker), and ultimately the use of a wheelchair may be required.
Some affected individuals may develop mild cognitive impairment, most commonly, mild attention and memory deficits. In some cases, cognitive problems may worsen, resulting in progressive loss of memory and intellectual abilities (dementia).
APBD is caused by a mutation in the GBE1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular domain, this can affect many organ systems of the body, including the brain.
APBD has traditionally been classified as an autosomal recessive disorder. Broadly, recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from both parents. However, although APBD has been classified as an autosomal recessive disorder, there have been many instances of APBD patients who carry the gene for the p.Y329S mutation in the heterozygous state (meaning they have the mutation in one copy of the GBE1 gene, but not in the other copy). These heterozygous patients should be asymptomatic carriers, yet they manifest symptoms of the disease and have been labeled as “manifesting heterozygotes”. These patients also have no other mutation in the 16 exons of the gene. Exons are specific segments of a gene that code for the protein produced by that gene. A study in 2015 (Akman et al. 2015) has discovered that in a cohort of 35 patients with APBD, 16 heterozygous patients for the p.Y329S mutation were compound heterozygotes for 2 mutations: p.Y329S as well as a mutation that affects a noncoding segment of DNA on the gene (intronic mutation). This intronic mutation resulted in a shortened (truncated) unstable protein. No patient had this intronic mutation in both copies of the GBE1 gene, possibly suggesting perinatal mortality.
A chart of all 40 known GBE1 gene mutations can be found here:
The two most common mutations are p.Y329S and the deep intronic mutation.
The GBE1 gene contains instructions for producing (encoding) a protein called glycogen branching enzyme or GBE. This enzyme is required for the proper building (synthesis) of glycogen, which is a complex sugar that normally is broken down (metabolized) into a simple sugar known as glucose. Glucose is one of the main sources of energy in the body. Because of mutations in the GBE1 gene, there are insufficient levels of functional GBE. This results in improperly formed glycogen, which accumulates in various tissues of the body in a form called polyglucosan bodies. Specifically, polyglucosan bodies may accumulate in star-shaped nerve cells known as astrocytes in the brain and spinal cord (central nervous system) and in the processes (axons) that extend from nerve cells as well as in peripheral nerves and the lung, heart, liver, kidneys, and even skin cells. Tissue reduction (atrophy), tissue loss (necrosis), and/or loss of the fatty sheath surrounding nerve fibers (demyelination) may occur. The mechanism by which the polyglucosan bodies cause nerve damage in axons is suggested to be their clogging (Lossos et al. 2009), which, in a neuronal culture, leads to cell death (Kakhlon et al. 2013).
Adult polyglucosan body disease is a rare disorder that appears to affect males and females in equal proportions. Familial clustering is observed in about 30% of cases especially among Ashkenazi Jewish populations. More than 50 cases have been reported in the medical literature.
A diagnosis is made based upon a thorough clinical evaluation, identification of characteristic findings, a detailed patient history, and a variety of specialized tests.
Clinical Testing and Workup
Direct examination of tissue by a pathologist (electron and light microscopy) can help reach a definitive diagnosis. The microscopic examination of a sample of nerve tissue (sural nerve biopsy) reveals the presence of characteristic polyglucosan bodies. These bodies may also be present in other disorders and may occur in the normal course of aging. However, in individuals with APBD, the polyglucosan bodies are mostly and almost uniquely in the fibers extending from nerve cells (axons) as opposed to the body of the cells (where they are in Lafora disease). The presence of the amorphic polyglucosan bodies in the fibers is key to the diagnosis. However, as taking a sural nerve biopsy is an uncomfortable surgical procedure, a biochemical test of GBE activity in blood cells combined with the genetic screening has replaced the biopsy as the diagnostic method of choice.
Reduced activity of the enzyme, GBE, can be measured (assayed) in cultured skin cells (fibroblasts) or white blood cells (lymphocytes) found in the peripheral blood. In addition, a specialized imaging technique known as magnetic resonance imaging (MRI) may show abnormalities in the conduction tissue (white matter) of the brain.
In some cases, molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the GBE1 gene known to cause APBD, but is available only as a diagnostic service at specialized laboratories.
To date, there is no specific therapy for individuals with APBD. Treatment is aimed at the specific symptoms present in each person. Treatment generally requires a team approach and may include neurologists, general internists, urologists, specialists in behavioral neurology, specialists in physical medicine rehabilitation, psychologists, and medical social workers. Genetic counseling is recommended for affected individuals and their families.
Antispasmodic medications may be considered for individuals with neurogenic bladder. Some individuals may require the use of an indwelling or an in-and-out catheter in order to drain urine from the bladder. An indwelling catheter is a tube that is inserted into the bladder and left in place in order to drain urine. An in-and-out catheter is used one time to drain urine and then removed.
Physical and occupational therapy is of benefit for some affected individuals. The disorder may progress so that devices that help affected people to continue their daily activities, such as braces, hand splints, limb supports, or wheelchairs, are necessary. Affected individuals who are restricted to bed may be made more comfortable with adjustable beds, water mattresses, and/or sheepskin mattress pads.
In cases with cognitive impairment, behavioral modification and other cognitive aids may be considered.
Researchers studied the use of triheptanoin, a tasteless, synthetic oil, for the treatment of individuals with adult polyglucosan body disease. Triheptanoin was added to the diet of affected individuals and, in initial studies, affected individuals experienced stabilization of disease progression and limited functional improvement (Roe et al. 2010). However, a larger scale (23 patients), recently concluded clinical study unfortunately did not demonstrate a significant clinical effect of triheptanoin on APBD patients, mainly due to the high inter-patient heterogeneity (Schiffmann et al. 2017).
Other therapeutic approaches are being studied in cell cultures and animal models of the disease. A clinical trial based on these approaches has been initiated.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact:
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